Description: Legislation passed in 1996
mandated that the EPA develop and implement a screening strategy for assessing
the risk associated with endocrine disrupting chemicals (EDCs). Recommendations
of the Endocrine Disruptor Screening and Testing Advisory Committee (EDSTAC)
focused on development of priority-setting approaches and Tier 1 screening
methods, initially for assessing estrogenic activity, that would guide
the more limited application of Tier 2 animal testing. Priority setting
primarily refers to quantitative structure-activity relationship (QSAR)
methods for assessing the potential estrogenic activity of chemicals for
which test data are unavailable. Included on the list of Tier 1 screening
methods is the in vitro estrogen receptor (ER) competitive-binding assay,
which provides quantitative assessment of a chemical's ability to bind
to the ER. Researchers within FDA's National Center for Toxicological
Research (NCTR) generated a database of experimental ER binding results
for the express purpose of developing improved QSAR models to predict
ER binding affinities. The NCTR ER database consists of 232 chemicals
(131 active and 101 inactive) selected a priori based on structural characteristics
and tested in a well validated and standardized in vitro rat uterine cytosol
ER competitive-binding assay [Blair et al. 2000; Branham et al., 2002].
The database is a structurally diverse set of natural, synthetic, and
environmental estrogens covering most known estrogenic classes and spanning
a wide range of biological activity. It represents the largest published
ER binding database of same-assay results generated in a single laboratory.

The main citation of Fang et al. (2001) surveys the NCTR ER database
from a chemical class based, structure-activity relationship (SAR) perspective.
Qualitative SAR characteristics of the NCTR ER database are discussed
and a set of general hierarchical rules for identifying potential estrogens
are presented. For construction of the DSSTox NCTRER SDF, the original
NCTR ER database has been augmented with chemical class and SAR information
abstracted from Fang et al. (2001). Information on the percent purity
and purchasing source for all chemicals are not included in the DSSTox
SDF, but can be obtained from the original NCTR ER Source database and
Main Citations listed below. For the DSSTox SDF files, we have supplemented
the measured ER relative binding affinity for each chemical (LOG_ER_RBA
or ER_RBA) with chemical class assignment to one of 6 major estrogenic
classes further divided into 20 subclasses (ChemClass_ERB). Mean
ER_RBA values for activities within the 6 major estrogenic classes (Mean_ER_RBA_ChemClass) are reported, along with a qualitative activity
measure, ActivityCategory_ER_RBA. In addition, log (octanol/water
partition coefficient) values (LOGP) are provided. A brief narrative
SAR rationale pertaining to ER RBA patterns observed by Fang et al. (2001)
for each of the 20 subclasses within the database are provided in the
field, ActivityCategory_Rationale_ChemClass_ERB. Finally, we approximate the decision
flowchart for identification of ER binders, presented in Fig. 14 of Fang
et al. (2001), with 6 indicator (1=yes, 0=no) fields: F1_Ring,
F2_AromaticRing, F3_PhenolicRing, F4_Heteroatom,
F5_Phenol3nPhenyl, F6_OtherKeyFeatures. Further details
on the flowchart rules for predicting ER binding, the criteria for chemical
structure class and subclass assignments, corresponding class-based SAR
rationales for ER binding, and additional references are provided in the
NCTRER Field Definition File offered for download below.

The original NCTR ER database, from which the expanded DSSTox NCTRER
was formed, is contained within a larger Endocrine Disruptor Knowledge
Base (EDKB) accessible from the FDA Source Website. That website provides online access to an ORACLE-backed relational database
comprised of in vitro and in vivo experimental data for about 2000 natural
and synthetic compounds, much of this extracted from the literature and
representing testing in many laboratories. Data are included for biological
assays that measure estrogenic and androgenic activity. Estrogenic endpoints
include in vitro assays for estrogen receptor competitive binding affinity,
cell proliferation, and reporter-gene assays, and in vivo assays for uterotrophic
activity (i.e., uterine weight gain and vaginal cornification). The database
also contains a bibliography of over 1200 citations, many of which include
abstracts.

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Source Website: For further information
on the original NCTR ER database and to gain relational database access
to a wider body of information on EDCs, users are encouraged to visit the
NCTR Endocrine Disruptor Knowledge Base website at http://edkb.fda.gov/index.html

Guidance for Use: A user of the DSSTox
NCTRER SDF files is encouraged to consult the NCTR EDC Source Website
http://edkb.fda.gov/index.html
and the main and supporting literature citations provided therein and
above. Some discrepancies were noted in ER binding values reported in
the earlier publications compared to those listed at the NCTR EDC website;
the latter values are the most current and accurate and are those included
in the DSSTox NCTRER SDF files. Although not reported in the original
publications, three compounds were tested in citrate form and one was
tested in a salt form. We represent information on the tested forms of
the chemicals in the main NCTRER file. The NCTRER Field Definition File
contains essential documentation and should be downloaded with, and accompany
any use of the DSSTox NCTRER SDF file. The NCTRER Log File provides database
summary information (field, chemical counts, etc.) and a description of
procedures and quality assurance checks used in SDF file creation. In
addition, the Log File documents modifications incorporated into version/revision
updates of the DSSTox NCTRER SDF file. For additional information on DSSTox
SDF files and their use in Chemical Relational Databases, see More
on SDF and More on CRDs.
To report errors in any NCTRER documentation or SDF data file, click on
File Error Report here
or below.

Version 4b Update: NCTRER_v4b includes minor structure changes/modifications and two new summary activity fields for use in PubChem and structure-activity relationship studies: ActivityOutcome_NCTRER (entries of active, inactive, or inconclusive) and ActivityScore_NCTRER (INTEGER[0-100]). In addition, the new STRUCTURE_InChIKey field (25 character abbreviated InChI for use in structure-indexing applications) has been added as a DSSTox Standard Chemical Field to all DSSTox files.

For more information and version history, consult the NCTRER_LogFile in the Download Table below.

File Download Notes: The following files are offered in the DownLoad table below:

Log File (PDF) provides SDF data file version history and summary information (field, chemical counts, etc.), and a description of procedures and quality assurance checks used in SDF file creation;Field Definition File (PDF or MS Word doc file) provides field definitions and essential documentation, and should be downloaded with and accompany any use of the DSSTox SDF file; Structure Data File (SDF) is the main DSSTox product, providing the complete inventory of chemical structures, DSSTox Standard Chemical Fields, and all Source-specific data fields
[Note: the structure field is blank for all records containing mixtures or undefined substances]; Data Table MS Excel (MS Office 2003) file contains the full SDF data contents in spreadsheet table form, minus the chemical structure field [file created with CambridgeSoft ChemFinder plug-in to MS Excel 2003];Structures Table (PDF) file contains a tiled format graphical view of all chemical structures contained in the SDF file, annotated with TestSubstance_CASRN and truncated TestSubstance_ChemicalName field entries for the tested form of the chemical [file created with ACD ChemFolder, ver. 10.01, ACD Labs].

You will need Adobe Acrobat Reader, available as a free download, to view the Adobe PDF files on this page. See EPA's PDF page to learn more about PDF, and for a link to the free Acrobat Reader.

Return to Top Acknowledgements: The original DSSTox SDF file
for the NCTRER was expanded from an original SDF file kindly provided
by the NCTR Source, Weida Tong. The file was converted to DSSTox format
by ClarLynda Williams (EPA/NC Central Univ Student COOP; EPA) with the
assistance of Jamie Burch (EPA/NC Central Univ Student COOP) and Ann Richard
(EPA). Additional ER-related data fields were added by Ann Richard (EPA)
in collaboration with Weida Tong and Hong Fang, both of NCTR. Finally,
we thank Rob Dewoskin (EPA) for review of all documentation and Stephen
Little (EPA) for providing a few missing CAS numbers, and for his careful
review of the documentation and helpful suggestions. All subsequent QA review and structure modifications to NCTRER_v2 and later versions were carried out by Maritja Wolf (Lockheed Martin, Contractor for EPA).

Disclaimer: Every effort is made to ensure
that DSSTox SDF files and associated documentation are error-free, but
neither the DSSTox Source collaborators nor the EPA DSSTox project team
make guarantees of accuracy, nor are any of these persons to be held liable
for any subsequent use of these public data. The contents of this webpage
and supporting documents have been subjected to review by the National
Health and Environmental Effects Research Laboratory and approved for
publication. Approval does not signify that the contents reflect the views
of the Agency, nor does mention of trade names or commercial products
constitute endorsement or recommendation for use. See additional disclaimers.